Peptide inhibitors of interleukin-23 receptor and their use to treat inflammatory diseases

Abstract

The present invention provides novel peptide inhibitors of the interleukin-23 receptor, and related compositions and methods of using these peptide inhibitors to treat or prevent a variety of diseases and disorders, including inflammatory bowel diseases.

What is claimed is: 
     
         1 . A monocyclic peptide inhibitor of an interleukin-23 receptor, or a pharmaceutically acceptable salt or solvate thereof, wherein the peptide inhibitor comprises an amino acid sequence of Formula (I′):
   X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16  (I′)
 
 wherein: 
 X3 is absent or any amino acid; 
 X4 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen (sulfoxide); 
 X5 and X6 is any amino acid; 
 X7 is unsubstituted Trp, or Trp substituted with substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 X8 is any amino acid, 
 X9 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen (sulfoxide); 
 X10 is unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; and 
 X11 is 2 Quin, 3 Quin, 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 1-Nal, unsubstituted Trp, or Trp substituted with:
 aryl, unsubstituted or substituted with halo, alkyl, cyano, haloalkyl, hydroxy, alkoxy, haloalkyloxy, phenyl, or substituted phenyl; 
 
 each of X12, X13, and X14 is independently any amino acid; 
 X15 is absent or any amino acid; 
 X16 is absent or any amino acid; and 
 provided that 
 i) at least one of X7 and X11 is Trp substituted with substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and 
 ii) the C-terminal amino acid is other than Aib, 2 Pal, 3 Pal, 4 Pal, 5 Pyal, THP, His, (D)His, substituted His, substituted (D)His, Phe, substituted Phe, substituted (D)Phe, a-MePhe, substituted a-MePhe, Trp, substituted Trp, substituted or unsubstituted Tyr, substituted or unsubstituted (D)Tyr, substituted or unsubstituted aMeTyr, substituted or unsubstituted (D)aMeTyr, b-hPhe, Sarc, bAla, 1-Nal, aMe(1-Nal), substituted 1-Nal, 2-Nal, aMe(2-Nal), substituted 2-Nal, or N-substituted Asn; and 
 wherein the peptide inhibitor is cyclized via a bond between X4 and X9; and 
 the peptide inhibitor inhibits the binding of an interleukin-23 (IL-23) to an IL-23 receptor. 
 
     
     
         2 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 1 , wherein the peptide inhibitor comprises an amino acid sequence of Formula (Ia′):
   X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16  (Ia′)
 
 wherein: 
 X3 is absent or any amino acid; 
 X4 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen (sulfoxide); 
 X5 and X6 is any amino acid; 
 X7 is unsubstituted Trp, or Trp substituted with substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 X8 is any amino acid, 
 X9 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen (sulfoxide); 
 X10 is unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; and 
 X11 is 2 Quin, 3 Quin, 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 1-Nal, unsubstituted Trp, or Trp substituted with:
 aryl, unsubstituted or substituted with halo, alkyl, cyano, haloalkyl, hydroxy, alkoxy, haloalkyloxy, phenyl, or substituted phenyl; 
 
 each of X12, X13, and X14 is independently any amino acid; 
 X15 is absent or any amino acid; 
 X16 is absent or any amino acid; and 
 provided that 
 i) at least one of X7 and X11 is Trp substituted with substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and 
 ii) the C-terminal amino acid is Asn, (D)Leu, (D)Lys, or Aib; and 
 wherein the peptide inhibitor is cyclized via a bond between X4 and X9; and 
 the peptide inhibitor inhibits the binding of an interleukin-23 (IL-23) to an IL-23 receptor. 
 
     
     
         3 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 1 , wherein the peptide inhibitor comprises an amino acid sequence of Formula (Ib′):
   X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16  (Ib′)
 
 wherein: 
 X3 is absent or any amino acid; 
 X4 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen (sulfoxide); 
 X5 and X6 is any amino acid; 
 X7 is unsubstituted Trp, or Trp substituted with substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 X8 is any amino acid, 
 X9 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen (sulfoxide); 
 X10 is unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; and 
 X11 is 2 Quin, 3 Quin, 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 1-Nal, unsubstituted Trp, or Trp substituted with:
 aryl, unsubstituted or substituted with halo, alkyl, cyano, haloalkyl, hydroxy, alkoxy, haloalkyloxy, phenyl, or substituted phenyl; 
 
 each of X12, X13, and X14 is independently any amino acid; 
 X15 is absent or any amino acid; 
 X16 is absent or any amino acid; and 
 provided that 
 i) at least one of X7 and X11 is Trp substituted with substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and 
 ii) the C-terminal amino acid is (D)Lys; and 
 wherein the peptide inhibitor is cyclized via a bond between X4 and X9; and 
 the peptide inhibitor inhibits the binding of an interleukin-23 (IL-23) to an IL-23 receptor. 
 
     
     
         4 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 1 , wherein the peptide inhibitor comprises an amino acid sequence of Formula (Ic′):
   X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16  (Ic′)
 
 wherein: 
 X3 is absent or any amino acid; 
 X4 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen (sulfoxide); 
 X5 and X6 is any amino acid; 
 X7 is unsubstituted Trp, or Trp substituted with substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 X8 is any amino acid, 
 X9 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen (sulfoxide); 
 X10 is unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; and 
 X11 is 2 Quin, 3 Quin, 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 1-Nal, unsubstituted Trp, or Trp substituted with:
 aryl, unsubstituted or substituted with halo, alkyl, cyano, haloalkyl, hydroxy, alkoxy, haloalkyloxy, phenyl, or substituted phenyl; 
 
 each of X12, X13, and X14 is independently any amino acid; 
 X15 is (D)Leu, or (D)Lys; and 
 X16 is absent; and 
 provided that 
 at least one of X7 and X11 is Trp substituted with substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and 
 the peptide inhibitor inhibits the binding of an interleukin-23 (IL-23) to an IL-23 receptor. 
 
     
     
         5 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 1 , wherein the peptide inhibitor comprises an amino acid sequence of Formula (Id′):
   X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16  (Id′)
 
 wherein: 
 X3 is absent or any amino acid; 
 X4 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen (sulfoxide); 
 X5 and X6 is any amino acid; 
 X7 is unsubstituted Trp, or Trp substituted with substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 X8 is any amino acid, 
 X9 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen (sulfoxide); 
 X10 is unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; and 
 X11 is 2 Quin, 3 Quin, 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 1-Nal, unsubstituted Trp, or Trp substituted with:
 aryl, unsubstituted or substituted with halo, alkyl, cyano, haloalkyl, hydroxy, alkoxy, haloalkyloxy, phenyl, or substituted phenyl; 
 
 each of X12, X13, and X14 is independently any amino acid; 
 X15 is Asn, (D)Leu, or (D)Lys; 
 X16 is absent; and 
 provided that 
 i) at least one of X7 and X11 is Trp substituted with substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and 
 ii) the C-terminal amino acid is Asn, (D)Leu, (D)Lys, or Aib; and 
 wherein the peptide inhibitor is cyclized via a bond between X4 and X9; and 
 the peptide inhibitor inhibits the binding of an interleukin-23 (IL-23) to an IL-23 receptor. 
 
     
     
         6 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 1 , wherein the peptide inhibitor comprises an amino acid sequence of Formula (Ie′):
   X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16  (Ie′)
 
 wherein: 
 X3 is absent or any amino acid; 
 X4 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen (sulfoxide); 
 X5 and X6 is any amino acid; 
 X7 is unsubstituted Trp, or Trp substituted with substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 X8 is any amino acid, 
 X9 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen (sulfoxide); 
 X10 is unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; and 
 X11 is 2 Quin, 3 Quin, 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 1-Nal, unsubstituted Trp, or Trp substituted with:
 aryl, unsubstituted or substituted with halo, alkyl, cyano, haloalkyl, hydroxy, alkoxy, haloalkyloxy, phenyl, or substituted phenyl; 
 
 each of X12, X13, and X14 is independently any amino acid; 
 X15 is (D)Leu, or (D)Lys; and 
 X16 is absent; and 
 provided that 
 at least one of X7 and X11 is Trp substituted with substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and 
 the peptide inhibitor inhibits the binding of an interleukin-23 (IL-23) to an IL-23 receptor. 
 
     
     
         7 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 1 , wherein the peptide inhibitor comprises an amino acid sequence of Formula (I′):
   X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X13-X14-X15-X16  (I′)
 
 wherein: 
 X3-X6, and X12-X16 are as described in  claim 1 ; 
 X7 is unsubstituted Trp, or Trp substituted with:
 aryl, unsubstituted or substituted with halo, alkyl, cyano, haloalkyl, hydroxy, alkoxy, haloalkyloxy, phenyl, or substituted phenyl; 
 
 X8 is Gln, alpha-MeLys, alpha-MeLeu, alpha-MeLys(Ac), Lys(Ac), or homo-Lys(Ac); 
 X9 is Abu, Cys, or Pen; 
 X10 is Phe substituted with 2-aminoethoxy, or 2-acetylaminoethoxy; and 
 X11 is 3 Quin, 2-Nal, or Trp 7-aza; and
 provided that at least one of X7 and X11 is Trp substituted with aryl, unsubstituted or substituted with halo, alkyl, cyano, haloalkyl, hydroxy, or alkoxy; 
 
 the C-terminal amino acid is other than Aib, 2 Pal, 3 Pal, 4 Pal, 5 Pyal, THP, His, (D)His, substituted His, substituted (D)His, Phe, substituted Phe, substituted (D)Phe, a-MePhe, substituted a-MePhe, Trp, substituted Trp, substituted or unsubstituted Tyr, substituted or unsubstituted (D)Tyr, substituted or unsubstituted aMeTyr, substituted or unsubstituted (D)aMeTyr, b-hPhe, Sarc, bAla, 1-Nal, aMe(1-Nal), substituted 1-Nal, 2-Nal, aMe(2-Nal), substituted 2-Nal, or N-substituted Asn; and 
 wherein the peptide inhibitor inhibits the binding of an interleukin-23 (IL-23) to an IL-23 receptor. 
 
     
     
         8 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 1 , wherein the peptide inhibitor comprises an amino acid sequence of Formula (I′):
   X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16  (I′)
 
 wherein: 
 X3, and X12-X16 are as described in  claim 1 ; 
 X4 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen (sulfoxide); 
 X5 is Cit, Glu, Gly, Leu, Ile, beta-Ala, Ala, Lys, Asn, Pro, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Gln, Asp, Ser, or Cys; 
 X6 is Thr, Aib, Asp, Dab, Gly, Pro, Ser, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, alpha-MeThr, alpha-MeSer, or Val; 
 X7 is unsubstituted Trp, or Trp substituted with:
 aryl, unsubstituted or substituted with halo, alkyl, cyano, haloalkyl, hydroxy, alkoxy, haloalkyloxy, phenyl, or substituted phenyl; 
 
 X8 is Gln, alpha-Me-Lys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), 1-Nal, 2-Nal, or Trp; 
 X9 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen (sulfoxide), wherein if X4 is Abu then X9 is Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen (sulfoxide), and wherein if X9 is Abu, then X4 is Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen or Pen (sulfoxide); 
 X10 is unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; and 
 X11 is 3 Quin, 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 1-Nal, unsubstituted Trp, or Trp substituted with:
 aryl, unsubstituted or substituted with halo, alkyl, cyano, haloalkyl, hydroxy, alkoxy, haloalkyloxy, phenyl, or substituted phenyl; 
 
 wherein the peptide inhibitor is cyclized via a bond between X4 and X9, and provided that at least one of X7 and X11 is Trp substituted with:
 aryl, unsubstituted or substituted with halo, alkyl, cyano, haloalkyl, hydroxy, alkoxy, haloalkyloxy, phenyl, or substituted phenyl; 
 
 the C-terminal amino acid is other than Aib, 2 Pal, 3 Pal, 4 Pal, 5 Pyal, THP, His, (D)His, substituted His, substituted (D)His, Phe, substituted Phe, substituted (D)Phe, a-MePhe, substituted a-MePhe, Trp, substituted Trp, substituted or unsubstituted Tyr, substituted or unsubstituted (D)Tyr, substituted or unsubstituted aMeTyr, substituted or unsubstituted (D)aMeTyr, b-hPhe, Sarc, bAla, 1-Nal, aMe(1-Nal), substituted 1-Nal, 2-Nal, aMe(2-Nal), substituted 2-Nal, or N-substituted Asn; and 
 wherein the peptide inhibitor inhibits the binding of an interleukin-23 (IL-23) to an IL-23 receptor. 
 
     
     
         9 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 7 , wherein X4 or X9 is Cys, (D)Cys, alpha-MeCys, (D)Pen, or Pen; and the bond between X4 and X9 is a disulfide bond. 
     
     
         10 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 7 - 8 , wherein X4 is Cys, (D)Cys, or alpha-MeCys. 
     
     
         11 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 7 - 8 , wherein X4 is (D)Pen, Pen, or Pen (sulfoxide). 
     
     
         12 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 7 - 8 , wherein X4 is Pen. 
     
     
         13 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 1 - 12 , wherein X9 is Cys, (D)Cys, or alpha-MeCys. 
     
     
         14 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 1 - 12 , wherein X9 is Pen or (D)Pen. 
     
     
         15 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 1 - 12 , wherein X9 is Pen. 
     
     
         16 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 7 , wherein X4 is Pen and X9 is Pen, and the bond is a disulfide bond. 
     
     
         17 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 7 , wherein X4 or X9 is Abu; and the bond is a thioether bond. 
     
     
         18 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of either of  claims 7  or  17 , wherein X4 is Abu. 
     
     
         19 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 1 - 13  or  17 - 18 , wherein X9 is Cys, (D)Cys, or alpha-MeCys. 
     
     
         20 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 1 - 12  or  14 - 18 , wherein X9 is Pen or (D)Pen. 
     
     
         21 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 1 - 12 ,  14 - 18  or  20 , wherein X9 is Pen. 
     
     
         22 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 1 - 13  or  17 - 19 , wherein X9 is Cys. 
     
     
         23 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 1 - 13 ,  14 ,  15  or  17 - 22 , wherein X4 is Abu and X9 is Cys or Pen, and the bond is a thioether bond. 
     
     
         24 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 1 - 23 , wherein X3 is absent. 
     
     
         25 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 1 , wherein the peptide inhibitor comprises an amino acid sequence of Formula (IIa) (IIb), or (IIc):
   Pen-X5-X6-X7-X8-Pen-X10-X11-X12-X13-X14-X15-X16  (IIa);
     Abu-X5-X6-X7-X8-Cys-X10-X11-X12-X13-X14-X15-X16  (IIb); or
     Abu-X5-X6-X7-X8-Pen-X10-X11-X12-X13-X14-X15-X16  (IIc)
   wherein X5-X8 and X10-X16 are as described in  claim 1 , and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond, an Abu-Cys thioether bond, or an Abu-Pen thioether bond.   
     
     
         26 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 1 - 25 , wherein X5 is Asn, Gln, Ser, or Glu. 
     
     
         27 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 1 - 25 , wherein X5 is Asn, or Gln. 
     
     
         28 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 1 - 25 , wherein X5 is Asn. 
     
     
         29 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 1 , wherein the peptide inhibitor comprises an amino acid sequence of Formula (IIIa), (IIIb), (IIIc), or (IIId):
   Pen-Asn-X6-X7-X8-Pen-X10-X11-X12-X13-X14-X15-X16  (IIIa);
     Pen-Gln-X6-X7-X8-Pen-X10-X11-X12-X13-X14-X15-X16  (IIIb);
     Abu-Asn-X6-X7-X8-Cys-X10-X11-X12-X13-X14-X15-X16  (IIIc); or
     Abu-Gln-X6-X7-X8-Pen-X10-X11-X12-X13-X14-X15-X16  (IIId)
   wherein X6-X8 and X10-X16 are as described in  claim 1 ; and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond, an Abu-Cys thioether bond, or an Abu-Pen thioether bond.   
     
     
         30 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 1 - 29 , wherein X6 is Thr. 
     
     
         31 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 1 , wherein the peptide inhibitor comprises an amino acid sequence of Formula (IVa), (IVb), (IVc), or (IVd):
   Pen-Asn-Thr-X7-X8-Pen-X10-X11-X12-X13-X14-X15-X16  (IVa);
     Pen-Gln-Thr-X7-X8-Pen-X10-X11-X12-X13-X14-X15-X16  (IVb);
     Abu-Asn-Thr-X7-X8-Cys-X10-X11-X12-X13-X14-X15-X16  (IVc); or
     Abu-Gln-Thr-X7-X8-Pen-X10-X11-X12-X13-X14-X15-X16  (IVd)
   wherein X7-X8 and X10-X16 are as described in  claim 1 ; and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond, an Abu-Cys thioether bond, or an Abu-Pen thioether bond.   
     
     
         32 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 1 - 31 , wherein X8 is Gln, alpha-MeLys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), 1-Nal, 2-Nal, or Trp. 
     
     
         33 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 1 - 32 , wherein X8 is Gln, alpha-Me-Lys, alpha-MeLys(Ac), or Glu. 
     
     
         34 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 1 - 32 , wherein X8 is Gln or Lys(Ac). 
     
     
         35 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 1 , wherein the peptide inhibitor comprises an amino acid sequence of Formula (Va), (Vb), (Vc), or (Vd):
   Pen-Asn-Thr-X7-Gln-Pen-X10-X11-X12-X13-X14-X15-X16  (Va);
     Pen-Gln-Thr-X7-Gln-Pen-X10-X11-X12-X13-X14-X15-X16  (Vb);
     Abu-Asn-Thr-X7-Gln-Cys-X10-X11-X12-X13-X14-X15-X16  (Vc); or
     Abu-Gln-Thr-X7-Gln-Pen-X10-X11-X12-X13-X14-X15-X16  (Vd)
   wherein X7-X8 and X10-X16 are as described in  claim 1 ; and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond, an Abu-Cys thioether bond, or an Abu-Pen thioether bond.   
     
     
         36 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 1 - 35 , wherein X10 is Phe substituted with 2-aminoethoxy, or 2-acetylaminoethoxy. 
     
     
         37 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 1 - 35 , wherein X10 is Phe, Phe[4-(2-aminoethoxy)], Phe[4-(2-acetylaminoethoxy)], or Phe(4-CONH 2 ). 
     
     
         38 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 1 - 35 , wherein X10 is Phe[4-(2-aminoethoxy)], or Phe[4-(2-acetylaminoethoxy)]. 
     
     
         39 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 1 , wherein the peptide inhibitor comprises an amino acid sequence of Formula (VIa), (VIb), (VIc), or (VId):
   Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-X12-X13-X14-X15-X16  (VIa);
     Pen-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-X12-X13-X14-X15-X16  (VIb);
     Abu-Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-X11-X12-X13-X14-X15-X16  (VIc); or
     Abu-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-X12-X13-X14-X15-X16  (VId)
   wherein X7 and X11-X16 are as described in  claim 1 ; [F(4-2ae)] is Phe[4-(2-aminoethoxy)];   and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond, an Abu-Cys thioether bond, or an Abu-Pen thioether bond.   
     
     
         40 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 1 - 39 , wherein the peptide inhibitor comprises an amino acid sequence of Formula (II′):
   X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16  (II′)
 
 wherein 
 X4-X11, and X16 are as described in  claim 1 ; X12 is 4-amino-4-carboxy-tetrahydropyran (THP), alpha-MeLys, alpha-MeLeu, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, Ala, cyclohexylAla, Lys, or Aib; 
 X13 is Aib, Glu, Cit, Gln, Lys(Ac), alpha-MeArg, alpha-MeGlu, alpha-MeLeu, alpha-MeLys, alpha-Me-Asn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Lys, pegylated Lys, b-homoGlu, or Lys(Y2-Ac), wherein Y2 is an amino acid; 
 X14 is Asn, 2-Nap, Aib, Arg, Cit, Asp, Phe, Gly, Lys, Leu, Ala, (D)Ala, beta-Ala, His, Thr, n-Leu, Gln, Ser, (D)Ser, Tic, Trp, alpha-MeGln, alpha-MeAsn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Lys(Ac); and 
 X15 is 2 Pal, 3 Pal, His, Asn, Arg, Leu, Val, Pro, (D)Pro, Ile, NMeArg, Aib, (D)Leu, (D)Lys, beta-Ala, Cit, Gln, Asp, alpha-MeGln, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or absent. 
 
     
     
         41 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 1 , wherein the peptide inhibitor comprises an amino acid sequence of Formula (VIIa), (VIIb), or (VIIc):
   Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-X12-X13-X14-X15-X16  (VIIa);
     Abu-Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-X11-X12-X13-X14-X15-X16  (VIIb); or
     Abu-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-X12-X13-X14-X15-X16  (VIIc)
   wherein X7 and X11 are as described in  claim 1 ; X12-X15 are as described in  claim 37 ; X16 is absent or any amino acid; and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond, an Abu-Cys thioether bond, or an Abu-Pen thioether bond.   
     
     
         42 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 41 , wherein X12 is 4-amino-4-carboxy-tetrahydropyran (THP), alpha-MeLys, alpha-MeLeu, Ala, cyclohexylAla, Lys, or Aib. 
     
     
         43 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 41 , wherein X12 is 4-amino-4-carboxy-tetrahydropyran (THP), alpha-MeLys, or alpha-MeLeu. 
     
     
         44 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 41 , wherein X12 is alpha-MeLeu. 
     
     
         45 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 40 - 44 , wherein X13 is Glu, Gln, Lys(Ac), or Lys. 
     
     
         46 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 40 - 44 , wherein X13 is Gln, Lys(Ac), or Lys. 
     
     
         47 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 40 - 44 , wherein X13 is Lys(Ac), or Lys. 
     
     
         48 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 40 - 44 , wherein X13 is Lys(Ac). 
     
     
         49 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 1 , wherein the peptide inhibitor comprises an amino acid sequence of Formula (VIIIa), (VIIIb) or (VIIIc):
   Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-aMeLeu-K(Ac)—X14-X15-X16  (VIIIa);
     Abu-Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-X11-aMeLeu-K(Ac)—X14-X15-X16  (VIIIb); or
     Abu-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-aMeLeu-K(Ac)—X14-X15-X16  (VIIIc)
   wherein X7 and X11 are as described in  claim 1 ; X14, and X15 are as described in  claim 37 ;   and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond, an Abu-Cys thioether bond, or an Abu-Pen thioether bond.   
     
     
         50 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 40 - 49 , wherein X14 is Asn. 
     
     
         51 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 40 - 49 , wherein X15 is Asn, (D)Lys, 2 Pal, or 3 Pal. 
     
     
         52 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 1 , wherein the peptide inhibitor comprises an amino acid sequence of Formula (IXa), (IXb), or (IXc):
   Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-[α-MeLeu]-K(Ac)-Asn-Asn-X16  (IXa);
     Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-[α-MeLeu]-K(Ac)-Asn-Asn-X16  (IXb); or
     Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-X11-[α-MeLeu]-K(Ac)-Asn-Asn-X16  (IXc)
   wherein X7 and X11 are as described in  claim 1 ; X16 is absent or any amino acid; and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond, an Abu-Cys thioether bond, or an Abu-Pen thioether bond.   
     
     
         53 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 1 - 52 , wherein X7 is Trp substituted with:
 aryl, unsubstituted or substituted with halo, alkyl, cyano, haloalkyl, hydroxy, alkoxy, haloalkyloxy, phenyl, or substituted phenyl;   and X11 is as described in  claim 1 .   
     
     
         54 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 1 - 52 , wherein X11 is Trp substituted with:
 aryl, unsubstituted or substituted with halo, alkyl, cyano, haloalkyl, hydroxy, alkoxy, haloalkyloxy, phenyl, or substituted phenyl;   and X7 is as described in  claim 1 .   
     
     
         55 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 1 , wherein the peptide inhibitor comprises an amino acid sequence of Formula (Xa), (Xb), (Xc), (Xd), (Xe), or (Xf):
   Pen-Asn-Thr-W′-Gln-Pen-[F(4-2ae)]-X11-aMeLeu-K(Ac)-Asn-Asn-X16  (Xa);
     Pen-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-W′-aMeLeu-K(Ac)-Asn-Asn-X16  (Xb);
     Abu-Asn-Thr-W′-Gln-Cys-[F(4-2ae)]-X11-aMeLeu-K(Ac)-Asn-Asn-X16  (Xc);
     Abu-Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-W′-aMeLeu-K(Ac)-Asn-Asn-X16  (Xd);
     Abu-Asn-Thr-W′-Gln-Pen-[F(4-2ae)]-X11-aMeLeu-K(Ac)-Asn-Asn-X16  (Xe); or
     Abu-Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-W′-aMeLeu-K(Ac)-Asn-Asn-X16  (Xf)
   wherein X7 and X11 are as described in  claim 1 ; X16 is absent or any amino acid;   W′ is Trp substituted with:
 aryl, unsubstituted or substituted with halo, alkyl, cyano, haloalkyl, hydroxy, alkoxy, haloalkyloxy, phenyl, or substituted phenyl; 
   and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond, an Abu-Cys thioether bond, or an Abu-Pen thioether bond.   
     
     
         56 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 1 - 55 , wherein X11 is 3 Quin, 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), or 1-Nal. 
     
     
         57 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 1 - 55 , wherein X11 is 3 Quin, 2-Nal or 1-Nal. 
     
     
         58 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 1 - 55 , wherein X11 is 2-Nal. 
     
     
         59 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 1 - 55 , wherein X7 is unsubstituted Trp. 
     
     
         60 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 1 , wherein the peptide inhibitor comprises an amino acid sequence of Formula (XIa), (XIb), (XIc), (XId), (XIe), or (XIf):
   Pen-Asn-Thr-W′-Gln-Pen-[F(4-2ae)]-[2-Nal]-aMeLeu-K(Ac)-Asn-Asn-X16  (XIa);
     Pen-Asn-Thr-W-Gln-Pen-[F(4-2ae)]-W′-aMeLeu-K(Ac)-Asn-Asn-X16  (XIb);
     Abu-Asn-Thr-W′-Gln-Cys-[F(4-2ae)]-[2-Nal]-aMeLeu-K(Ac)-Asn-Asn-X16  (XIc);
     Abu-Asn-Thr-W-Gln-Cys-[F(4-2ae)]-W′-aMeLeu-K(Ac)-Asn-Asn-X16  (XId);
     Abu-Asn-Thr-W′-Gln-Pen-[F(4-2ae)]-[2-Nal]-aMeLeu-K(Ac)-Asn-Asn-X16  (XIe); or
     Abu-Asn-Thr-W-Gln-Pen-[F(4-2ae)]-W′-aMeLeu-K(Ac)-Asn-Asn-X16  (XIf)
   wherein W′ is Trp substituted with: aryl, unsubstituted or substituted with halo, alkyl, cyano, haloalkyl, hydroxy, alkoxy, haloalkyloxy, phenyl, or substituted phenyl; and
 X16 is absent or any amino acid; 
   and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond, an Abu-Cys thioether bond, or an Abu-Pen thioether bond.   
     
     
         61 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 1 - 59 , wherein X7 is aryl, unsubstituted or substituted with halo, alkyl, cyano, haloalkyl, hydroxy, alkoxy, haloalkyloxy, phenyl, or substituted phenyl; heteroaryl, unsubstituted or substituted with halo, alkyl, cyano, haloalkyl, hydroxy, or alkoxy. 
     
     
         62 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 1 - 59 , wherein X7 is Trp substituted with i) phenyl, unsubstituted or substituted with cyano, halo, alkyl, haloalkyl, aryl hydroxy, alkoxy, or haloalkoxy; or ii) thienyl. 
     
     
         63 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 1 - 59 , wherein X7 is Trp substituted with phenyl, unsubstituted or substituted with Me, Et, n-Pr, i-Pr, t-Bu, OMe, OEt, Cl, F, CF3, OCF3, phenyl, substituted phenyl, or amido. 
     
     
         64 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 1 - 59 , wherein X7 is Trp substituted with unsubstituted phenyl; or unsubstituted thienyl. 
     
     
         65 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 1 - 59 , wherein X7 is Trp substituted with 7-Ph. 
     
     
         66 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 1 - 59 , wherein X7 is Trp substituted with unsubstituted 7-Ph. 
     
     
         67 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 1 - 66 , wherein the peptide inhibitor comprises the structure of Formula (Z):
   R′—X—R 2   (Z)
   or a pharmaceutically acceptable salt or solvate thereof, wherein   R 1  is a bond, hydrogen, Ac, a C1-C6 alkyl, a C6-C12 aryl, a C6-C12 aryl-C1-6 alkyl, a C1-C20 alkanoyl, and including PEGylated versions alone or as spacers of any of the foregoing;   X is the amino acid sequence of any of Formula (I′), Formulas (Ia′)-(Ie′), Formulas (II)(II′), or (II″), or Formulas (IIa)-(XIf), or an amino acid sequence set forth in Table E1; and   R 2  is OH or NH 2 .   
     
     
         68 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 1 - 66 , wherein the peptide inhibitor comprises the structure of Formula (Z′):
   R 1 —X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-R 2   (Z′)
 
 or a pharmaceutically acceptable salt or solvate thereof, wherein 
 R 1  is a bond, hydrogen, a C1-C6 alkyl, a C6-C12 aryl, a C6-C12 aryl, a C1-C6 alkyl, a C1-C20 alkanoyl, and including PEGylated versions alone or as spacers of any of the foregoing; 
 X3-X16 is the amino acid sequence of any of Formula (I′), Formulas (Ia′)-(Ie′), Formulas (II), (II′), or (II′), or Formulas (IIa)-(XIf), or an amino acid sequence set forth in Table E1; 
 and R 2  is OH or NH 2 . 
 
     
     
         69 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 67  or  68  wherein R 1  is H or C1-C20 alkanoyl. 
     
     
         70 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 67  or  claim 68 , wherein R 1  is H or Ac. 
     
     
         71 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 67  or  claim 68 , wherein R 1  is Ac. 
     
     
         72 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 55 - 60 , wherein W′ is Trp substituted with:
 aryl, unsubstituted or substituted with halo, alkyl, cyano, haloalkyl, hydroxy, alkoxy, haloalkyloxy, phenyl, or substituted phenyl; 
 and the substitution is at 4-, 5-, 6- or 7-position. 
 
     
     
         73 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 55 - 60 , wherein W′ is Trp substituted with phenyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and the substitution is at 4-, 5-, 6- or 7-position. 
     
     
         74 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 55 - 60 , wherein W′ is Trp substituted with 7-Ph. 
     
     
         75 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 55 - 60 , wherein W′ is Trp substituted with 7-Ph, wherein Ph is substituted with alkyl, alkoxy, trifluroalkoxy, or halo. 
     
     
         76 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 55 - 60 , wherein W′ is Trp substituted with 7-Ph, wherein Ph is substituted with Me, Et, i-Pr, OCF3, CF3, or F. 
     
     
         77 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 55 - 60 , wherein W′ is Trp substituted with 7-Ph, wherein Ph is substituted with 3-Me, 3-iPr, 3-OCF3, 4-F, or 3-OMe. 
     
     
         78 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 55 - 60 , wherein W′ is Trp substituted with 7-thienyl. 
     
     
         79 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 1 , wherein the peptide inhibitor comprises an amino acid sequence set forth in any one of SEQ ID NOs:1-19, optionally wherein the peptide inhibitor comprises a disulfide bond between Pen and Pen, Cys and Pen, or Pen and Cys, or a thioether bond between Abu and Pen or Abu and Cys. 
     
     
         80 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 1 - 79 , further comprising a conjugated chemical substituent. 
     
     
         81 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 80 , wherein the conjugated chemical substituent is a lipophilic substituent or a polymeric moiety. 
     
     
         82 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 80 , wherein the conjugated chemical substituent is Ac, Palm, gamaGlu-Palm, isoGlu-Palm, PEG2-Ac, PEG4-isoGlu-Palm, (PEG) 5 -Palm, succinic acid, glutaric acid, pyroglutaric acid, benzoic acid, IVA, octanoic acid, 1,4 diaminobutane, isobutyl, or biotin. 
     
     
         83 . The peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of  claim 80 , wherein the conjugated chemical substituent is a polyethylene glycol with a molecular mass of 400 Da to 40,000 Da. 
     
     
         84 . A polynucleotide comprising a sequence encoding the peptide inhibitor of any one of  claims 1 - 83 . 
     
     
         85 . A vector comprising the polynucleotide of  claim 84 . 
     
     
         86 . A pharmaceutical composition comprising the peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 1 - 83 , and a pharmaceutically acceptable carrier, excipient, or diluent. 
     
     
         87 . The pharmaceutical composition of  claim 86 , further comprising an enteric coating. 
     
     
         88 . The pharmaceutical composition of  claim 87 , wherein the enteric coating protects and releases the pharmaceutical composition within a subject's lower gastrointestinal system. 
     
     
         89 . A method for treating an Inflammatory Bowel Disease (IBD), ulcerative colitis, Crohn's disease, Celiac disease (nontropical Sprue), enteropathy associated with seronegative arthropathies, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, colitis associated with radio- or chemo-therapy, colitis associated with disorders of innate immunity as in leukocyte adhesion deficiency-1, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, and Wiskott-Aldrich Syndrome, pouchitis resulting after proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, psoriasis, psoriatic arthritis, or graft versus host disease in a subject, comprising providing to the subject an effective amount of the peptide inhibitor or peptide inhibitor or pharmaceutically acceptable salt or solvate thereof of any one of  claims 1 - 83 , or the pharmaceutical composition of any one of  claims 86 - 88 . 
     
     
         90 . The method of  claim 89 , wherein the pharmaceutical composition is provided to the subject by an oral, parenteral, intravenous, peritoneal, intradermal, subcutaneous, intramuscular, intrathecal, inhalation, vaporization, nebulization, sublingual, buccal, parenteral, rectal, intraocular, inhalation, topically, vaginal, or topical route of administration. 
     
     
         91 . The method of  claim 89  for treating Inflammatory Bowel Disease (IBD), ulcerative colitis, or Crohn's disease, wherein the pharmaceutical composition is provided to the subject orally. 
     
     
         92 . The method of  claim 89  for treating psoriasis, wherein the pharmaceutical composition is provided to the subject orally, topically, parenterally, intravenously, subcutaneously, peritoneally, or intravenously.